Novel compounds useful for modulating abnormal cell proliferation

ABSTRACT

There is described compounds of Formula I, and salts, solvates and hydrates thereof:  
                 
 
wherein: R 1 , R 2  and R 3  are each independently selected from OH, C 1-6 alkyl, OC 1-6 alkyl, OC(O)C 1-6 alkyl, C(O)OC 1-6 alkyl, NH 2 , NH—C 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), SH, SC 1-6 alkyl, NO 2 , CF 3 , OCF 3  and halogen; and Ar is an aromatic or heteroaromatic group chosen from benzene, naphthalene, quinoline, isoquinoline, indole, pyridine, pyrasine, pyrimidine, imidazole, furan and thiophene, unsubstituted or substituted with  1 - 4  substituents independently selected from OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-3 alkylenedioxy, NH 2 , NH—C 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), SH, S—C 1-6 alkyl, NO 2 , CF 3 , OCF 3  and halogen. The compounds of Formula I are useful: in therapeutic methods and compositions for modulating cell proliferation, in diagnostic assays and as research tools.

CROSS-REFERENCE TO RELATED APPLICATION

Continuation Application from U.S. application Ser. No. 10/940,010.

BACKGROUND OF THE INVENTION

1. Field of the Invention

In one of its aspects, the present invention relates to a group of novelcompounds, particularly useful for modulating abnormal cellproliferation. In another of its aspects, the present invention relatesto a pharmaceutical composition comprising the novel compounds. In yetanother of its aspects, the present invention relates to a methodmodulating cell proliferation using the novel compounds. In yet anotherof its aspects, the present invention relates to a process forproduction of the novel compounds.

2. Description of the Prior Art

A wide range of growth factors coordinate cell proliferation anddifferentiation. Malignant cells arise as a result of a stepwiseprogression of events that include the unregulated expression of growthfactors or components of their signaling pathways. Tyrosinephosphorylation events initiated by receptor, cytoplasmic and nuclearkinases and regulated by phosphatases are central to these processes.Mutation, hyper-activation, translocation and overexpression of proteintyrosine kinases are all associated with tumorigenesis. In addition toincreasing proliferative rates and immortalizing cells, overexpressionof tyrosine kinases can lead to morphological transformation and causeanchorage independence, contributing to the promotion of migratoryability and possibly the induction of metastases.

Certain compounds with structures based upon mimicry of ATP orphosphotyrosine have been shown to be effective kinase inhibitors. Thosebased upon phosphotyrosine have been demonstrated to be the morespecific tyrosine kinase inhibitors. Because of their ability to inhibittyrosine phosphorylation, these compounds may alter cell responses togrowth factors or other process driven by tyrosine kinase activity,including unregulated growth as the result of tyrosine kinaseoverexpression, mutation, or translocation. Inhibition of tyrosinekinases occupying a central role in proliferative signaling pathways, orin pathways regulating cell cytoskeletal structure, even temporary orincomplete inhibition, may be sufficient to switch a cancerous cell froma proliferative cycle into programmed cell death, or apoptosis. Death byapoptosis is most often observed upon effective treatment with tyrosinekinase inhibitors.

Selective inhibition of specific tyrosine kinases offers a method oftargeting cancerous cell growth with a high degree of specificity andminimal toxicity to normally growing cells and tissues. Thus, specificinhibitors of tyrosine kinases have great potential as clinicalanti-cancer treatments. A number of small molecules which act astyrosine kinase inhibitors have been identified. For example, certainphenyl acrylonitrile compounds have been described as tyrosine kinaseinhibitors, effective to inhibit cell proliferation. See, for example,any of U.S. Pat. Nos. 5,891,917, 5,217,999, 5,773,476, 5,935,993,5,656,655, 5,677,329 and 5,789,427.

Inhibition of tyrosine kinases offers one mechanism by which cellproliferation can be inhibited. One of skill in the art will appreciatethat other mechanisms of inhibition may also be involved.

Certain advances in the art are described in International PublicationNumber Number WO 01/79158 [Roifman et al. (Roifman #1)] InternationalPublication Number Number WO 03/062190 [Roifman et al. (Roifman #2)].

While the teachings of Roifman #1 and Roifman #2 represent importantadvances in the art, there is an ongoing need in the art to identifyfurther compounds that inhibit cell proliferation.

DISCLOSURE OF THE INVENTION

It is an object of the present invention to obviate or mitigate at leastone of the above-mentioned disadvantages of the prior art.

In one of its aspects the present invention provides, the presentinvention provides a compound of Formula I, and salts, solvates andhydrates thereof:

wherein:

R¹, R² and R³ are each independently selected from OH, C₁₋₆alkyl,OC₁₋₆alkyl, OC(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, NH₂, NH—C₁₋₆alkyl,N(C₁₋₆alkyl)(C₁₋₆alkyl), C(O)NHC₁₋₆alkyl, C(O)N(C₁₋₆alkyl)(C₁₋₆alkyl),SH, SC₁₋₆alkyl, NO₂, CF₃, OCF₃ and halogen;

Ar is an aromatic or heteroaromatic group chosen from benzene,naphthalene, quinoline, isoquinoline, indole, pyridine, pyrasine,pyrimidine, imidazole, furan and thiophene, unsubstituted or substitutedwith 1-4 substituents independently selected from OH, C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₃alkylenedioxy, NH₂, NH—C₁₋₆alkyl,N(C₁₋₆alkyl)(C₁₋₆alkyl), SH, S—C₁₋₆alkyl, NO₂, CF₃, OCF₃ and halogen

Non-limiting examples of preferred compounds of Formula I may beselected from the group comprising:5-(4-Hydroxy-3-methoxyphenyl)-penta-2E,4E-dienoic acid benzylamide(CRD-81); 5-(3,4-Dihydroxyphenyl)-penta-2E,4E-dienoic acid benzylamide(CRD-82); 5-(4-Hydroxy-3,5-dimethoxyphenyl)-penta-2E,4E-dienoic acid3,4-dihydroxybenzylamide (CRD-84); and5-(4-Hydroxy-3-ethoxyphenyl)-penta-2E,4E-dienoic acid3,4-dihydroxybenzylamide (CRD-85), the chemical structure of each ofwhich is provided in the Examples below.

Another aspect of the present invention relates to a pharmaceuticalcomposition comprising, as the active ingredient, one or more compoundsof Formula I, together with a pharmaceutically acceptable carriertherefor.

In accordance with a further aspect of the present invention, there isprovided a method for modulating cell proliferation, preferablyinhibiting cell proliferation comprising administering an effectiveamount of a compound of the invention to a cell or animal in needthereof. The invention also includes a use of a compound of theinvention to modulate cell proliferation, preferably inhibit cellproliferation. The invention further includes a use of a compound of theinvention to prepare a medicament to modulate cell proliferation,preferably inhibit cell proliferation.

In a preferred embodiment the present invention provides a method ofinhibiting the proliferation of a cancer cell comprising administeringan effective amount of a compound of the invention to a cell or animalin need thereof. The cancer cell treated may be any type of cancerincluding a leukemia, a lymphoma, myeloma, metastatic carcinoma, sarcomaor any other malignant transformation or any other malignancy. Theinvention also includes a use of a compound of the invention to modulatecancer cell proliferation, preferably inhibit cancer cell proliferation.The invention further includes a use of a compound of the invention toprepare a medicament to modulate cancer cell proliferation, preferablyinhibit cancer cell proliferation.

In another aspect, the invention provides a method of modulatingtyrosine kinase activity in a cell by administering an effective amountof a compound of the invention. In a further aspect, the inventionprovides a method of inhibiting tyrosine kinase activity in a cell byadministering an effective amount of a compound of the invention. Thepresent invention also provides a use of a compound of the invention tomodulate, preferably inhibit, tyrosine kinase activity. The presentinvention further provides a use of a compound of the invention toprepare a medicament to modulate tyrosine kinase activity, preferablyinhibit tyrosine kinase activity. It is appreciated that the inhibitionof cell growth by the compounds of the invention may be effected byother mechanisms.

Other features and advantages of the present invention will becomeapparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples while indicating preferred embodiments of the invention aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

The term “C₁₋₆alkyl” as used herein means, unless otherwise stated,straight and/or branched chain alkyl radicals containing from one to sixcarbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl andthe like.

The term “C₁₋₆alkoxy” as used herein means, unless otherwise stated,straight and/or branched chain alkoxy radicals containing from one tosix carbon atoms and includes methoxy, ethoxy, propyloxy, isopropyloxy,t-butoxy and the like.

The term “C₁₋₄alkyl” as used herein means, unless otherwise stated,straight and/or branched chain alkyl radicals containing from one tofour carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyland the like.

The term “C₁₋₄alkoxy” as used herein means, unless otherwise stated,straight and/or branched chain alkoxy radicals containing from one tofour carbon atoms and includes methoxy, ethoxy, propyloxy, isopropyloxy,t-butoxy and the like.

The term “Ar” as used herein, means an unsubstituted or substituted aryland/or heteroaryl group which, in the case of heteroaryl, may contain upto two heteroatoms, wherein the constituents are independently selectedfrom the group consisting of OH, C₁₋₆alkyl, C₁₋₆alkoxy, NH₂,NH—C₁₋₆alkyl, N(C₁₋₆alkyl)(C₁₋₆alkyl), SH, S—C₁₋₆alkyl, NO₂, CF₃, OCF₃and halo, and includes unsubstituted or substituted phenyl, furyl,thienyl, indolyl, naphthyl, quinolyl and the like.

The term “halo” as used herein means halogen and includes chloro,flouro, bromo, iodo and the like.

The term “pharmaceutically acceptable salt” means an acid addition saltor a basic addition salt which is suitable for or compatible with thetreatment of patients.

The term “compound of the invention” as used herein includes anycompound of the Formula I as defined herein (including all salts,solvates or hydrates thereof) as well as a specific compound designatedherein as CRD-81, CRD-82, CRD-84 and CRD-84 (including all salts,solvates or hydrates thereof).

The term “salt”, as used in connection with the compounds of Formula I,is intended to encompass pharmaceutically acceptable acid addition saltand pharmaceutically acceptable base addition salt.

The term “pharmaceutically acceptable acid addition salt”, as usedherein, means any non-toxic organic or inorganic salt of any basecompounds represented by Formula I or any their intermediates.Illustrative inorganic acids which form suitable salts includehydrochloric, hydrobromic, sulfuric and phosphoric acids, as well asmetal salts such as sodium monohydrogen orthophosphate and potassiumhydrogen sulfate. Illustrative organic acids that form suitable saltsinclude mono-, di-, and tricarboxylic acids such as glycolic, lactic,pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric,ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids,as well as sulfonic acids such as p-toluene sulfonic and methanesulfonicacids. Either the mono or di-acid salts can be formed, and such saltsmay exist in either a hydrated, solvated or substantially anhydrousform.

In general, the acid addition salts of compounds of Formula I are moresoluble in water and various hydrophilic organic solvents, and generallydemonstrate higher melting points in comparison to their free baseforms. The selection of the appropriate salt will be known to oneskilled in the art. Other non-pharmaceutically acceptable salts, e.g.,oxalates, may be used, for example, in the isolation of compounds ofFormula I for laboratory use, or for subsequent conversion to apharmaceutically acceptable acid addition salt.

The term “pharmaceutically acceptable basic addition salt”, as usedherein, means any non-toxic organic or inorganic base addition salt ofany acid compounds represented by Formula I or their intermediates.Illustrative inorganic bases which form suitable salts include lithium,sodium, potassium, calcium, magnesium or barium hydroxide. Illustrativeorganic bases which form suitable salts include aliphatic, alicyclic oraromatic organic amines such as methylamine, trimethylamine and picolineor ammonia. The selection of the appropriate salt will be known to aperson skilled in the art.

The term “solvate”, as used herein, means a compound of Formula I, or apharmaceutically acceptable salt of a compound of Formula I, whereinmolecules of a suitable solvent are incorporated in the crystal lattice.A suitable solvent is physiologically tolerable at the dosageadministered. Examples of suitable solvents are ethanol, water and thelike.

When water is the solvent, the molecule is referred to as a “hydrate”.

The term an “effective amount” or a “sufficient amount” of an agent asused herein is that amount sufficient to effect beneficial or desiredresults, including clinical results, and, as such, an “effective amount”depends upon the context in which it is being applied. For example, inthe context of administering an agent that inhibits cancer cellproliferation, an effective amount of an agent is, for example, anamount sufficient to achieve such a reduction in cancer cellproliferation as compared to the response obtained withoutadministration of the agent.

As used herein, and as well understood in the art, “treatment” is anapproach for obtaining beneficial or desired results, including clinicalresults. Beneficial or desired clinical results can include, but are notlimited to, alleviation or amelioration of one or more symptoms orconditions, diminishment of extent of disease, stabilized (i.e. notworsening) state of disease, preventing spread of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.

“Palliating” a disease or disorder means that the extent and/orundesirable clinical manifestations of a disorder or a disease state arelessened and/or time course of the progression is slowed or lengthened,as compared to not treating the disorder.

The term “modulate”, as used herein, includes the inhibition orsuppression of a function or activity (such as cell proliferation) aswell as the enhancement of a function or activity.

To “inhibit” or “suppress” or “reduce” a function or activity, such ascancer cell proliferation, is to reduce the function or activity whencompared to otherwise same conditions except for a condition orparameter of interest, or alternatively, as compared to anotherconditions.

The term “animal”, as used herein, includes all members of the animalkingdom including humans and non-humans. The animal is preferably ahuman.

The term “a cell”, as used herein, includes a plurality of cells.Administering a compound to a cell includes in vivo, ex vivo and invitro treatment.

The term “cancer cells”, as used herein, includes all forms of cancer orneoplastic disease.

The present invention includes within its scope, prodrugs of thecompounds of the invention. In general, such prodrugs will be functionalderivatives of a compound of the invention which are readily convertiblein vivo into the compound from which it is notionally derived.Conventional procedures for the selection and preparation of suitableprodrugs are described, for example, in “Design of Prodrugs” ed. H.Bundgaard, Elsevier, 1985.

Some of the compounds of the invention may have at least one asymmetriccenter. Where the compounds according to the invention have oneasymmetric center, the may exist as enantiomers. Where the compounds ofthe invention possess two or more asymmetric centers, they mayadditionally exist as diastereomers. It is to be understood that allsuch isomers and mixtures thereof in any proportion are encompassedwithin the scope of the present invention.

The present invention includes radiolabeled forms of compounds of theinvention, for example, compounds of the invention labeled byincorporation within the structure ³H or ¹⁴C or a radioactive halogensuch as ¹²⁵I.

The compounds of the invention may, for example, be derived from anactivated cinnamyl compound and an activated cyano-substituted methylenecompound. A person skilled in the art, therefore, may wish to provide ageneric name for the compounds of the invention based on the cinnamylmoiety. However, generic nomenclature based on the formed acrylonitrilemoiety, for example, styryl acrylonitrile, would be more proper.

The compounds of the invention can be prepared by general process stepsestablished in the art for production of unrelated compounds. Therefore,compounds of the invention may be prepared by the reaction sequenceshown in Scheme 1:

Compounds of the general Formula (I), useful in the practice of thisinvention can be prepared by the condensation of aryl-substituted2E,4E-dienoic acids (II) with corresponding amine (III).

For example, these condensations may be carried out in appropriatesolvents, such as DMF-dichloromethane, in the presence of variousagents, useful in peptide chemistry, such as BOP(benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate). Aryl-substituted 2E,4E-dienoic acids can beobtained by Wittig condensation of appropriate aryl-substitutedcinnamaldehydes (IV) with methyl (triphenylphosphoranilydene)acetate.

At the end of this process, corresponding methyl Z,E-dienoate that isalso formed in this conditions, can be converted into the desirablemethyl E,E-dienoate (V) by treatment with iodine in dichloromethane.Methyl ester is hydrolyzed using standard procedures (Scheme 2).

In some cases the condensation outlined above may have to be modified byuse of protective groups, such as acetates or methyl ethers, to preventside reactions. At the end of reaction sequence, the protective groupscan be removed by processes analogous to those established in the art,for example as described in Greene T. W., Wuts P. G. M. ProtectiveGroups in Organic Synthesis. John Wiley & Sons, Third Edition, 1999(Scheme 3).

As stated above, an aspect of the present invention relates to apharmaceutical composition comprising, as the active ingredient, one ormore compounds of Formula I, together with a pharmaceutically acceptablecarrier therefor.

The dosage administered of the active ingredient will vary depending onthe use and known factors such as the pharmacodynamic characteristics ofthe particular substance, and its mode and route of administration; age,health, and weight of the individual recipient; nature and extent ofsymptoms, kind of concurrent treatment, frequency of treatment, and theeffect desired.

By way of general guidance, a daily dosage of the active ingredient canbe in the range of from about 0.01 to about 80 mg/kg of body weight,preferably from about 0.1 to about 20, more preferably from about 0.2 toabout 10 mg/kg of body weight. Ordinarily a dose of from about 0.5 toabout 50 mg/kg per day of the active ingredient divided doses one tomultiple times a day, preferably up to four times per day, or insustained release form is effective to obtain the desired results.

In the treatment methods and compositions of the present invention, theactive ingredient described in detail herein is (are) typicallyadministered for oral, topical, rectal, parenteral, local, inhalant orintracerebral use. In an embodiment of the invention, the substances areadministered in intranasal form via topical use of suitable intranasalvehicles, or via transdermal routes, using forms of transdermal skinpatches known to those of ordinary skill in that art. To be administeredin the form of a transdermal delivery system, the dosage administrationwill be continuous rather than intermittent throughout the dosageregimen. The substances can also be administered by way of controlled orslow release capsule system and other drug delivery technologies.

A preferred form of administration is oral. For example, for oraladministration in the form of a tablet or capsule, the activesubstance(s) can be combined with an oral, non-toxic, pharmaceuticallyacceptable, inert carrier such as lactose, starch, sucrose, glucose,methyl cellulose, magnesium stearate, dicalcium phosphate, calciumsulfate, mannitol, sorbitol and the like; for oral administration inliquid form, the oral active substances can be combined with any oral,non-toxic, pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like. Suitable binders, lubricants,disintegrating agents, and colouring agents can also be incorporatedinto the dosage form if desired or necessary. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth, orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, andthe like. Suitable lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride, and the like. Examples of disintegratorsinclude starch, methyl cellulose, agar, bentonite, xanthan gum, and thelike.

Gelatin capsules may contain the active substance and powdered carriers,such as lactose, starch, cellulose derivatives, magnesium stearate,stearic acid, and the like. Similar carriers and diluents may be used tomake compressed tablets. Tablets and capsules can be manufactured assustained release products to provide for continuous release of activeingredients over a period of time. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract. Liquid dosage forms fororal administration may contain colouring and flavouring agents toincrease patient acceptance.

Water, a suitable oil, saline, aqueous dextrose, and related sugarsolutions and glycols such as propylene glycol or polyethylene glycols,may be used as carriers for parenteral solutions. Such solutions alsopreferably contain a water soluble salt of the active ingredient,suitable stabilizing agents, and if necessary, buffer substances.Suitable stabilizing agents include antioxidizing agents such as sodiumbisulfate, sodium sulfite, or ascorbic acid, either alone or combined,citric acid and its salts and sodium EDTA. Parenteral solutions may alsocontain preservatives, such as benzalkonium chloride, methyl- orpropyl-paraben, and chlorobutanol.

The active ingredient described in detail herein can also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamellar vesicles, and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine, or phosphatidylcholines.

The active ingredient substances described in detail herein may also becoupled with soluble polymers which are targetable drug carriers.Examples of such polymers include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. The active ingredient substancesmay also be coupled to biodegradable polymers useful in achievingcontrolled release of a drug. Suitable polymers include polylactic acid,polyglycolic acid, copolymers of polylactic and polyglycolic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked oramphipathic block copolymers of hydrogels. The substances can also beaffixed to rigid polymers and other structures such as fullerenes orBuckeyballs.

Pharmaceutical compositions suitable for administration contain about 1milligram to 1500 milligrams of active ingredient per unit. In thesepharmaceutical compositions, the active ingredient will ordinarily bepresent in an amount of about 0.5-95% by weight based on the totalweight of the composition.

Suitable pharmaceutical carriers and methods of preparing pharmaceuticaldosage forms are described in Remington's Pharmaceutical Sciences, MackPublishing Company, a standard reference text in art of drugformulation.

As hereinbefore mentioned, the inventors have prepared novel compoundsof the Formula I. Accordingly, the present invention includes all usesof the compounds of the invention including their use in therapeuticmethods and compositions for modulating cell proliferation, their use indiagnostic assays and their use as research tools.

In one aspect, the present invention provides a method for modulatingcell proliferation comprising administering an effective amount of acompound of the invention to a cell or animal in need thereof.Preferably, the invention provides a method of inhibiting cellproliferation comprising administering an effective amount of a compoundof the invention to a cell or animal in need thereof. In particular, themethod of the invention is useful in inhibiting the proliferation ofabnormal but not normal cells. Abnormal cells include any type of cellthat is causative of or involved in a disease or condition and whereinit is desirable to modulate or inhibit the proliferation of the abnormalcell to treat the disease or condition. Examples of abnormal cellsinclude malignant or cancerous cells as well as cell thatover-proliferate in inflammatory conditions.

It has been determined that some of the compounds of the invention arevery effective at killing cancer cells while at the same time they donot kill normal cells. These properties make the compounds of theinvention extremely useful as anti-cancer agents. Accordingly, in oneembodiment, the present invention provides a method of inhibiting theproliferation of a cancer cell comprising administering an effectiveamount of a compound of the invention to a cell or animal in needthereof.

The cancer cell that can be treated with a compound of the invention maybe any type of cancer including, but not limited to, hematopoieticmalignancies, including leukemias, lymphomas, and myelomas as well asother types of cancer including sarcomas, carcinomas, melanomas,adenomas, nervous system cancers and genitourinary cancers. Examples ofleukemias include acute lymphoblastic leukemia (ALL), acute myclocyticleukemia (AML), chronic myeloid leukemia (CML), chronic lymphocyticleukemia (CLL) and juvenile myelo-monocytic leukemia (JMML). The typesof ALL that may be treated with the compounds of the invention includecells that express a bcr-abl fusion protein, such as Philadelphiapositive ALL cells, as well as Philadelphia negative ALL cells. Examplesof lymphomas include B-cell Burkitt's lymphoma, Hodgkin's lymphomas,non-Hodgkin's lymphomas, including the Ki-1 positive anaplastic largecell lymphomas, T cell lymphomas and rare lymphomas such as thehistiocytic lymphomas. Examples of myelomas include multiple myelomas.

Embodiments of the present invention will be described with reference tothe following Examples that are provided for illustrative purposes onlyand should not be used to construe or limit the scope of the invention.

In the Examples, a number of standard methods and materials were used.¹H NMR spectra were obtained on a Varian Unity Plus spectrometer (USA)at 500 MHz with tetramethylsilane (TMS, Me₄Si) as an internal standard(O). Electrospray mass spectra were recorded on an API III Plus triplequadrupole mass spectrometer (USA), with a direct introduction of thesamples into the ionization source. Thin layer chromatography wasperformed with UV-254 aluminum-backed TLC sheets of 0.25 mm thickness(Kieselgel 60 F₂₅₄, Merck, Germany). HPLC chromatograms and UV spectrawere obtained on a model 600 liquid chromatograph (Waters, USA) with amodel 996 PDA detector. The reagents were purchased from Aldrich (USA)and were used as received. Solvents were purchased from Caledon(Canada).

EXAMPLE 1 Methyl 5-(4-Acetoxy-3-methoxyphenyl)-penta-2E,4E-dienoate

To a solution of 880 mg (4.0 mmol) of 4-acetoxy-3-methoxycinnamaldehydein 100 mL of benzene, 2000 mg (6.0 mmol) of methyl(triphenylphosphoranilydene)acetate was added. The mixture was stirredat 80° C. for 4 h and passed through silica gel (eluent ethylacetate-hexane, 1:1) to remove the excess of the Wittig reagent.

The solvents were evaporated, the residue was dissolved in 800 nL ofdichloromethane, 12 (1 g) was added and the mixture was stirred at roomtemperature for 18 h. The mixture was worked up with 10% Na₂S₂O₅, theorganic layer was dried with Na₂SO₄ and evaporated. The residue wascrystallized from ethyl acetate-heptane.

The results were as follows:

-   -   a. Yield 990 mg (90%).    -   b. UV, λ_(max) 245, 317 nm.    -   c. ¹H-NMR (δ, ppm): 2.27 (s, 3H, OAc), 3.74 (s, 3H, COOMe), 3.90        (s, 3H, OMe), 6.08 (d, 1H, J=15.3 Hz, Hα olefinic), 7.09-7.15        (m, 3H, H⁵+Hγ olefinic+Hδ olefinic), 7.18 (dd, 1H, J 1.9 and 8.2        Hz, H⁶), 7.37 (d, 1H, J=1.9 Hz, H²), 7.47 (dd, 1H, J 10.5 and        15.3 Hz, Hp olefinic).

d. MS (m/z, rel. intensity, %): 203.0 (62), 235.3 ([M+NH₄—OAc]+, 58),245.3 ([M-OMe]+, 65), 277.0 ([M+H]⁺, 100), 294.1 ([M+NH₄]+, 45), 299.2([M+Na]⁺, 91), 335.2 ([M+OAc]+, 90).

EXAMPLE 2 Methyl 5-(4-Acetoxy-3,5-dimethoxyphenyl)-penta-2E,4E-dienoate

The compound was prepared based on the methodology used in Example Iusing 4-acetoxy-3,5-dimethoxycinnamaldehyde (500 mg, 2 mmol) and methyl(triphenylphosphoranilydene)acetate (1000 mg, 3 mmol).

The results were as follows:

-   -   a. Yield 525 mg (86%).    -   b. UV, λ_(max) 245, 322 nm.    -   c. ¹H-NMR (δ, ppm): 2.23 (s, 3H, OAc), 3.71 (s, 3H, COOMe), 3.83        (s, 6H, (OMe)₂), 6.04 (d, 1H, J=15.3 Hz, Hα olefinic), 6.96 (s,        2H, H²⁺⁶), 7.02 (d, 1H, J=15.6 Hz, Hδ olefinic), 7.12 (dd, 1H, J        10.9 and 15.6 Hz, Hγ olefinic), 7.42 (dd, 1H, J 10.9 and 15.3        Hz, Hβ olefinic).    -   d. MS (m/z, rel.intensity, %): 233.2 ([M+NH₄—OAc-MeOH]⁺, 44),        265.2 ([M+NH₄—OAc]+, 57), 275.2 ([M-OMe]+, 49), 307.2 ([M+H]⁺,        100), 324.3 ([M+NH₄]⁺, 75), 329.2 ([M+Na]⁺, 25).

EXAMPLE 3 5-(4-Hydroxy-3-methoxyphenyl)-penta-2E,4E-dienoic acid

Methyl 5-(4-Acetoxy-3-methoxyphenyl)-penta-2E,4E-dienoate (400 mg, 1.45mmol) [Example 1] was dissolved in 60 mL MeOH, 20 mL of 5% NaOH and 40mL of water were added, and the mixture was stirred for 24 h at roomtemperature. The mixture was acidified to pH 2 with 5% HCl, methanol wasevaporated and the compound was extracted with ethyl acetate. Theorganic layer was dried with Na₂SO₄ and evaporated.

The results were as follows:

-   -   a. Yield 320 mg (100%).    -   b. UV, λ_(max) 252, 345 mm.

EXAMPLE 4 5-(4-Hydroxy-3,5-dimethoxyphenyl)-penta-2E,4E-dienoic acid

The compound was prepared using the methodology used in Example 4 usingmethyl 5-(4-Acetoxy-3,5-dimethoxyphenyl)-penta-2E,4E-dienoate (400 mg,1.31 mmol) [Example 2].

The results were as follows:

-   -   a. Yield 328 mg (100%).    -   b. UV, λ_(max) 255, 348 nm.

EXAMPLE 5 5-(4-Hydroxy-3-methoxyphenyl)-penta-2E,4E-dienoic acidbenzylamide (CRD-81)

5-(4-Hydroxy-3-methoxyphenyl)-penta-2E,4E-dienoic acid (110 mg, 0.5mmol) [Example 3] was dissolved in 100 mL of DMF. Triethylamine (101 μl,1.0 mmol) was added, the mixture was cooled down to 0° C. and a solutionof benzylamine (109 μl, 1.0 mmol) was added followed by addition of BOPreagent (331 mg, 0.75 mmol) in 50 mL of dichloromethane.

The mixture was stirred for 15 min at 0° C. and for 2 h at roomtemperature. Dichloromethane was evaporated, 5% HCl was added, and theproduct was extracted with ethyl acetate. The organic layer was driedwith Na₂SO₄, evaporated, and the residue was purified on a column withsilica gel, eluent ethyl acetate-hexane. The fractions contained thedesired product were evaporated, the residue was dissolved inacetonitrile-water and lyophilized.

The results were as follows:

-   -   a. Yield 138 mg (89%).    -   b. UV, λ_(max) 248, 340 mm.    -   c. MS (m/z, rel.intensity, %): 310.4 ([M+H]⁺, 100), 332.5        ([M+Na]⁺, 45).

EXAMPLE 6 5-(3.4Dihydroxyphenyl)-penta-2E,4E-dienoic acid benzylamide(CRD-82)

To a solution of 5-(4-hydroxy-3-methoxyphenyl)-penta-2,4-dienoic acidbenzylamide (118 mg, 0.38 mmol) [Example 5] in 50 mL of dichloromethane,100 μl of boron tribromide (0.95 mmol) was added dropwise at −78° C. Themixture was stirred for 15 min at −78° C. and for 1 h at roomtemperature. Water (100 ML) was added, the organic layer was separated,dried with Na₂SO₄ and evaporated.

The residue was purified by HPLC (column Nova-Pak C18 19.0×300 mm,MeCN—H₂O, 40:60, FR 10.0 mL/min, retention time is 9.6 min).

The results were as follows:

-   -   a. Yield 70 mg (63%).    -   b. UV, λ_(max) 249 and 339 nm.    -   c. ¹H-NMR (δ, ppm): 4.47 (s, 2H, CH₂Ph′), 6.17 (d, 1H, J=15.0        Hz, Hα olefinic), 6.80 (m, 3H, H⁵+Hγ olefinic+Hδ olefinic), 6.88        (dd, 1H, J 2.1 and 8.2 Hz, H⁶), 7.05 (d, 1H, J=2.1 Hz, H²),        7.22-7.36 (m, 6H, Ph′+Hβ olefinic).    -   d. MS (m/z, rel. intensity, %): 296.7 ([M+H]⁺, 100), 318.4        ([M+NH₄]+, 50).

EXAMPLE 7 5-(4-Hydroxy-3,5-dimethoxyphenyl)-penta-2E,4E-dienoic acid3,4-dihydroxybenzylamide (CRD-84)

The compound was prepared based on the methodology in Example 5 using 38mg (0.15 mmol) of 5-(4-hydroxy-3,5-dimethoxyphenyl)-penta-2E,4E-dienoicacid [Example 4], 67 mg (0.30 mmol) of 3,4 dihydroxybenzylaminehydrobromide, 153 μl (1.5 mmol) of triethylamine, and 100 mg (0.23 mmol)of BOP reagent.

The results were as follows:

-   -   a. Yield 31 mg (55%).    -   b. UV, λ_(max) 253, 343 mm.    -   c. ¹H-NMR (δ, ppm): 3.85 (s, 6H, (OMe)₂), 4.30 (s, 2H, CH₂Ph′),        6.16 (d, 1H, J=14.9 Hz, Hα olefinic), 6.62 (dd, 1H, J 2.1 and        8.0 Hz, H^(6′)), 6.73 (d, 1H, J=8.0 Hz, H^(5′)), 6.81 (d, 1H,        J=2.1 Hz, H²), 6.83 (d, 1H, J=15.5 Hz, Hβ olefinic), 6.88 (s,        2H, ^(H2+6)), 6.90 (dd, 1H, J 10.4 and 15.5 Hz, Hγ olefinic),        7.33 (dd, 1H, J 10.4 and 14.9 Hz, Hβ olefinic).

d. MS (m/z, rel.intensity, %): 250.3 (15), 372.4 ([M+H]⁺, 100), 394.0([M+NH₄]+, 38).

EXAMPLE 8 5-(4-Hydroxy-3-methoxyphenyl)-penta-2E,4E-dienoic acid3,4-dihydroxybenzylamide (CRD-85)

The compound was prepared as described in Example 5 using 11 mg (0.05mmol) of 5-(4-hydroxy-3-methoxyphenyl)-penta-2E,4E-dienoic acid [Example3], 22 mg (0.10 mmol) of 3,4 dihydroxybenzylamine hydrobromide, 50 g(0.50 mmol) of triethylamine, and 33 mg (0.075 mmol) of BOP reagent.

The results were as follows:

-   -   a. Yield 10.2 mg (60%)    -   b. UV, λ_(max) 243, 339 mm.    -   c. MS (m/z, rel.intensity, %): 342.1 ([M+H]⁺, 100), 359.0        ([M+NH₄]+, 28), 363.9 ([M+Na]⁺, 40).

EXAMPLE 9 Killing of Philadelphia Positive Z119 Acute LymphoblasticLeukemia Cells by Low-Dose Test Compounds in Culture

Z119 cells were plated in 1 ml volumes at a density of 5×10⁴ cells/ml,in the absence of exogenous growth factors, into 35 mm petri dishes(Nunc, Gibco) containing IMDM (OCI, Toronto) plus 20% FCS (CanseraRexdale, ON.) in 0.9% (vol/vol) methylcellulose (Fluka, Switzerland)with the indicated concentration of for various test compounds describedabove. Cultures were set at 37° C., 5% CO₂ in a humidified atmosphere.Colonies consisting of more than 20 cells were counted at 7-9 days usingan inverted microscope. The results for various test compounds describedabove are presented in Table 1.

EXAMPLE 10 Effect of Test Compounds Upon Normal Bone MarrowDifferentiation in Culture

The CFU-GEMM assay was performed according to Fauser and Messner (1978,Blood, 52(6) 143-8) and Messner and Fausser (1980, Blut, 41(5) 327-33)with some variations. In brief, heparinized bone marrow cells werelayered over Percoll (1.077 gm/ml) (Pharmacia Fine Chemical, PiscatawayN.J.) and centrifuged at 400 g at 4° C. for 10 minutes to removeneutrophils and RBCs. The fractionated BM cells at 2×10⁻⁵ cells/ml werecultured in IMDM (OCI, Toronto) containing 0.9% (vol/vol)methylcellulose supplemented with 30% FCS (Cansera Rexdale, ON.) ornormal human plasma, a cocktail of cytokines containing G-CSF (10 ng/ml,Amgen), IL-3 (40 U/ml, Immunex), MGF (50 ng/ml, Immunex), Erythropoietin(2 u/ml, Epprex) or TPO (10 ng/ml, Amgen), 5×10⁻⁵ M Bβ-2-mercaptoethanoland the specified concentration of CR4. The culture mixture was platedin 1 ml volumes into 35 mm petri dishes and incubated at 37° C., 5% CO₂in a humidified atmosphere. All cultures were evaluated at 14 days forthe number of BFU-E colonies (defined as aggregates of more than 500hemoglobinized cells or, 3 or more erythroid subcolonies), CFU-GMcolonies (defined as granulocyte or monocyte-macrophage cells or both),CFU-Meg colonies (comprising 4 or more megakaryocytes) and CFU-GEMMcolonies (a mixed population comprising of all elements). The resultsfor various test compounds described above are presented in Table 1.

While the results in Table 1 for many of the test compounds are good, itis believed that the best results are those reported for compoundCRD-82.

While this invention has been described with reference to illustrativeembodiments and examples, the description is not intended to beconstrued in a limiting sense. Thus, various modifications of theillustrative embodiments, as well as other embodiments of the invention,will be apparent to persons skilled in the art upon reference to thisdescription. For example, many of the specific compounds of the presentinvention are encompassed by the general compounds of the Formula I. Forthe purposes of 35 U.S.C. §112 (first paragraph) and Article 123(2)/(3)EPC, it should be understood that the use of general compounds of theFormula I is shorthand for listing each specific compound encompassedthereby. Thus, general compounds of the Formula I are to be consideredsubstantively identical to a list of specific compounds derived from allpermutations and combinations covered by a general compound. As such,for the purposes of 35 U.S.C. §112 (first paragraph) and Article123(2)/(3) EPC, the right to use one or more provisos or disclaimers toclarify the definition of a general formula is expressly reserved (i.e.,having the effect of selecting members of a list of specific compoundsderived from a general compound). It is therefore contemplated that theappended claims will cover any such modifications or embodiments.

All publications, patents and patent applications referred to herein areincorporated by reference in their entirety to the same extent as ifeach individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by referencein its entirety. TABLE 1 ALL (Z 119) NBM (BFU-E) Code IC50, μM IC50, μMCRD-81 >1.0 >>10 CRD-82 =0.46 >25 CRD-84 >1.0 >>10 CRD-85 >1.0 >>10

1. A compound of Formula I, and salts, solvates and hydrates thereof:

wherein: R¹, R² and R³ are each independently selected from OH,C₁₋₆alkyl, OC₁₋₆alkyl, OC(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, NH₂,NH—C₁₋₆alkyl, N(C₁₋₆alkyl)(C₁₋₆alkyl), C(O)NHC₁₋₆alkyl,C(O)N(C₁₋₆alkyl)(C₁₋₆alkyl), SH, SC₁₋₆alkyl, NO₂, CF₃, OCF₃ and halogen;and Ar is an aromatic or heteroaromatic group chosen from benzene,naphthalene, quinoline, isoquinoline, indole, pyridine, pyrasine,pyrimidine, imidazole, furan and thiophene, unsubstituted or substitutedwith 1-4 substituents independently selected from OH, C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₃alkylenedioxy, NH₂, NH—C₁₋₆alkyl,N(C₁₋₆alkyl)(C₁₋₆alkyl), SH, S—C₁₋₆alkyl, NO₂, CF₃, OCF₃ and halogen. 2.5-(4-Hydroxy-3-methoxyphenyl)-penta-2E,4E-dienoic acid benzylamide(CRD-81), a salt thereof, a solvate thereof or a hydrate thereof. 3.5-(3,4-Dihydroxyphenyl)-penta-2E,4E-dienoic acid benzylamide (CRD-82), asalt thereof, a solvate thereof or a hydrate thereof. 4.5-(4-Hydroxy-3,5-dimethoxyphenyl)-penta-2E,4E-dienoic acid3,4-dihydroxybenzylamide (CRD-84), a salt thereof, a solvate thereof ora hydrate thereof.
 5. 5-(4-Hydroxy-3-methoxyphenyl)-penta-2E,4E-dienoicacid 3,4-dihydroxybenzylamide (CRD-85), a salt thereof, a solvatethereof or a hydrate thereof.
 6. A pharmaceutical composition comprisingthe compound defined in claim 1, together with a pharmaceuticallyacceptable carrier therefor.
 7. A method of modulating cellproliferation comprising administering an effective amount of thecompound defined in claim 1 to modulate cell proliferation to a cell oranimal in need thereof.
 8. A method of inhibiting cell proliferationcomprising administering an effective amount of the compound defined inclaim 1 to inhibit cell proliferation to a cell or animal in needthereof.
 9. The method defined in claim 8, wherein the cellproliferation that is inhibited is cancer cell proliferation.
 10. Themethod defined in claim 9, wherein the cancer cell is a hematopoieticcell
 11. A method of treating cancer comprising administering to ananimal in need thereof an effective amount of the compound defined inclaim
 1. 12. The method defined in claim 11, wherein cancer comprises ahematopoietic cell.
 13. The method defined in claim 9, wherein thecancer is a leukemia, a lymphoma or a myeloma.
 14. The method defined inclaim 13, wherein the leukemia is selected from the group comprisingacute lymphoblastic leukemia, aggressive Philadelphia+ leukemia, acutemyelocytic leukemia, chronic myeloid leukemia, chronic lymphocyticleukemia and juvenile myelomonocyte leukemia.
 15. The method defined inclaim 13, wherein the leukemia is acute lymphoblastic leukemia.
 16. Amethod of modulating cell proliferation comprising administering aneffective amount of a compound capable of modulating cell proliferationaccording to any one of claim 1 or a composition according to claim 6 toa cell or animal in need thereof.
 17. A method of inhibiting cellproliferation comprising administering an effective amount of a compoundcapable of inhibiting cell proliferation according to any one of claim 1or a composition according to claim 6 to a cell or animal in needthereof.
 18. A method of inhibiting cancer cell proliferation comprisingadministering an effective amount of a compound capable of inhibitingcancer cell proliferation according to any one of claim 1 or acomposition according to claim 6 to a cell or animal in need thereof.19. A method of treating cancer comprising administering an effectiveamount of a compound capable of inhibiting cancer cell proliferationaccording to any one of claim 1 or a composition according to claim 6 toa cell or animal in need thereof.
 20. The method defined in claim 18,wherein the cancer is a hematopoietic cell cancer.
 21. The methoddefined in claim 18, wherein the cancer is a leukemia, a lymphoma or amyeloma.
 22. The method defined in claim 21, wherein the leukemia isselected from the group comprising acute lymphoblastic leukemia,aggressive Philadelphia+ leukemia, acute myelocytic leukemia, chronicmyeloid leukemia, chronic lymphocytic leukemia or juvenile myelomonocyteleukemia.
 23. The method defined in claim 22, wherein the leukemia isacute lymphoblastic leukemia.
 24. Use of the compound defined in claim 1to treat cancer.